The art of tracing dietary fat in humans. Leanne Hodson

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1 The art of tracing dietary fat in humans Leanne Hodson

2 Dietary fat Other lipoproteins: IDL, LDL, HDL Hodson and Fielding linical Lipidology (2010)

3 Relationship between blood & dietary fatty acids Typically: Stronger and more consistent correlations for polyunsaturated fatty acids. Inconsistent correlations for saturated fatty acids. Weak correlations for monounsaturated fatty acids. Why? Hodson et al Prog Lipid Res (2008)

4 Possible reasons for inconsistent correlations Dietary assessment difficult to do - quality, database used, temporal relationship Some fatty acids ubiquitous in foods less variation in dietary intake How dietary intake assessed and reported How tissue/blood fatty acids expressed Differences in partitioning of fatty acids to different lipid pools Endogenous synthesis low variation in blood and tissues

5 Studying fatty acid metabolism: tracers Fatty acid tracers Tracers have been used to trace the fate of endogenous (preformed and synthesised) and exogenous (dietary) fatty acids onsiderations ost Natural abundance of isotope How delivering isotope (e.g. in food etc) Metabolic handling of tracer (e.g absorption) Order to give tracers (if giving multiple tracers) Sampling time frame / length of study day Background meal effects Repeat studies time between visits ommon form Stable isotope 1 H 2 H (0.02%) 12 (1.1%) 14 N 15 N (0.37%) 16 O 18 O (0.04%) 12 6 Protons 6 Neutrons 6 Protons 7 Neutrons

6 Stable isotopes 2 H 2 H 2 Oral ingestion -FA/TG 2 H-FA/TG 2 H 2 H

7 Dietary fat -FA/TG 2 H-FA/TG Other lipoproteins: IDL, LDL, HDL Hodson and Fielding linical Lipidology (2010)

8 Stable isotopes 2 H 2 H 2 Oral ingestion Whole body FA oxidation: -TG or FA -TG 2 H-TG -FA/TG 2 H-FA/TG -TG 2 H-TG 2 H 2 H

Question: Are there differences in the postprandial metabolic

h? Protocol Subjects: 6 male / 6 female Age (yr): 27 (2) BMI (kg/m

9 Question: Are there differences in the postprandial metabolic partitioning of the three most common fatty acids in blood over 24 h? Protocol Subjects: 6 male / 6 female Age (yr): 27 (2) BMI (kg/m 2 ): 23 (2) -18:2-18:1-16:0 Breakfast 75 g glucose Habitual diet h hylomicron-tg; VLDL-TG Plasma E, total PL; erythrocyte total PL Hodson et al (2008) AJP E and M Data presented mean (sem)

10 3 isotope study: Results Linoleate (L); Oleate (O); Palmitate (P) [U- ] fatty acids in chyomicron-tg (µmol/l) hylomicron-tg L vs O (P = ns) L vs P (P = ns) O vs P (P = ns) [U- ]fatty acids in VLDL-TG (µmol/l) VLDL-TG L vs O (P = 0.02) L vs P (P = ns) O vs P (P = 0.018) Time (h) Time (h) Hodson et al (2008) AJP E and M Data presented as mean (SE)

11 [U- ]fatty acids in plasma E (µmol/l) Linoleate (L); Oleate (O); Palmitate (P) Plasma holesteryl Ester L vs O (P < 0.001) L vs P (P < 0.001) O vs P (P = ns) Time (h) [U- ]fatty acids in erythrocyte PL (mg/l) [U- ]fatty acids in plasma PL (µmol/l) Plasma Phospholipids Erythrocyte Phospholipid L vs O (P = 0.008) L vs P (P = ns) O vs P (P < 0.001) Time (h) L vs O (P < 0.001) L vs P (P = 0.028) O vs P (P < 0.001) Hodson et al (2008) AJP E and M Time (h) Data presented as mean (SE)

12 Postprandial contribution of meal-derived fatty acids to specific blood lipid pools Proportion (%) Linoleate Oleate Palmitate The Taken VLDL-TG lack together of incorporation these findings of oleate suggest into that the 7 h 22 (2) 16 (2) 17 (2) blood in the lipid context fractions of monitoring (other than dietary plasma fatty TG) 24 h 8 (1) 3 (1) 3 (0) may acid help intakes, explain particularly why oleate the is previously 3 major Plasma E been dietary reported fatty 24 h acids, not 5 to (0.7) at be best a 2 good (0.2) erythrocytes biomarker 2 (0.1) of and intake; plasma particularly lipid fractions when compared reflecting to Plasma PL only recent, linoleate 24 rather h 10 (& than (2) palmitate). long-term 4 (0.4) intakes. 5 (0.5) Erythrocyte PL $ 24 h 2.6 (0.5) 0.5 (0.1) 0.7 (0.1) different from Linoleate (P < 0.05); different from Oleate (P < 0.05) Data presented as mean (SE) Hodson et al (2008) AJP E and M

13 Adipose Tissue: ability to reflect dietary change alculated half-life of fatty acids 1-1.5y (Beyen et al 1980) Using stable isotopes half-life of fatty acids 6-9 mth (Strawford et al 2004) hanging adipose tissue fatty acid composition: 20 weeks on high corn oil (40% TE) changes in AT fatty acids reported to be almost imperceptible (Hirsch et al 1960) Significant changes in n-6 fatty acids reported 5 wk after consumption of high n-6 PUFA diet (P/S ratio = 1.72) (Shepherd et al 1980) Significant changes in n-3 fatty acids reported after 9 wks of n-3 supplementation (Mostad et al 2006)

14 Adipose Tissue: Different sites, different answers? hanges in n-3 fatty acids MORE EVIDENT in ABDOMINAL compared to gluteal AT (Katan et al 1997) Katan et al (1997): n-3 supplementation study measure AT fatty acids at 180 d Abdomen Possible explanation for discrepancy Gluteal between published results: uptake of dietary fatty acids is different in these two depots. Shepherd et al (1980) Mostad et al (2006) Hirsch et al (1960) Is there evidence for this hypothesis?

15 Studying the physiology of subcutaneous adipose tissue Frayn KN et al. lin Sci (1989) McQuaid SE et al. Obesity (2010)

Net movement of fatty acids in and out of

8 12 16 20 24 Time (h) Net fat mobilisation

16 Net movement of fatty acids in and out of adipose tissue (transcapillary flux) Meal Meal Meal Net fat storage nmol.100 g -1 min Time (h) Net fat mobilisation McQuaid et al (2011) Diabetes AU x Fat Mass = total meal storage of fat

17 Proportion of the meal fat deposited in subcutaneous abdominal adipose tissue 60 P=0.007 P= Lean % Abdominally-obese 0 Meal 1 Meal 2 Meal 3 McQuaid et al (2011) Diabetes

18 Subcutaneous adipose tissue: abdominal vs gluteofemoral Meal Femoral a.t. Net fat storage Net fat storage Abdominal a.t. Net fat mobilisation McQuaid et al (2010) Diabetes

19 Subcutaneous adipose tissue: abdominal vs gluteofemoral Transcapillary flux ( mol.min g tissue -1 ) Meals Time (min) A moment Net fat on storage the lips Net fat storage a lifetime on the hips? Net fat mobilisation Femoral a.t. Abdominal a.t. Manolopoulos et al: unpublished work

20 What is hepatic de novo lipogenesis? Synthesis of fatty acids and triglyceride from non-lipid substrates Starts with small precursor molecule (usually 2 acetyl group) is gradually lengthened by 2 until it gives rise to 16 and 18 products Pathway for disposing of excess carbohydrate Process is stimulated by high carbohydrate availability and insulin

acid (16:0) SD Palmitoleic acid (16:1 n-7) Elongation Stearic acid (18:0) Oleic acid (18:1 n-9)

21 De novo lipogenesis (DNL) De novo lipogenesis Glucose Dietary fatty acids Adipose tissue Pyruvate Systemic NEFA Acetyl oa Myristic acid (14:0) A1 Malonyl oa FAS Elongation Palmitic acid (16:0) SD Palmitoleic acid (16:1 n-7) Elongation Stearic acid (18:0) Oleic acid (18:1 n-9) Vaccenic acid (18:1 n-7cis) A = acetyl-oa carboxylase FAS = fatty acid synthase SD = stearoyl-oa desaturase

DNL and fatty acid composition aution: Palmitic the lipogenic acid (16:0)

Linoleic when acid a (18:2 high n-6) saturated is an fat essential diet

Lipogenic index = ratio of 16:0 / 18:2 n-6 Hepatic DNL been shown to

diet DNL + diet 16:0 Stable-isotope work has 30 mol% reported that the

(from de novo lipogenesis) to VLDL-TG 35 mol% VLDL-TG palmitate in the

5 mol% Diet 18:2 n-6 VLDL-TG adults but higher in individuals with

22 DNL and fatty acid composition aution: Palmitic the lipogenic acid (16:0) index is the (16:0 end / 18:2 product n-6) is of not DNL meaningful Linoleic when acid a (18:2 high n-6) saturated is an fat essential diet is consumed fatty acid as hepatic DNL may not increase. Lipogenic index = ratio of 16:0 / 18:2 n-6 Hepatic DNL been shown to robustly increase (with use of tracers) after a high carbohydrate (sugar) diet DNL + diet 16:0 Stable-isotope work has 30 mol% reported that the contribution of DNL Diet 18:2 n-6 + diet 16:0 newly synthesised palmitate (from de novo lipogenesis) to VLDL-TG 35 mol% VLDL-TG palmitate in the fasting state is <10% in healthy 8.5 mol% Diet 18:2 n-6 VLDL-TG adults but higher in individuals with insulin-resistance, hypertriglyceridemia, type 2 diabetes, or non-alcoholic fatty liver Lipogenic disease Index = (NAFLD) 3.5 Lipogenic Index = mol%

23 [ ]palmitate in S f lipoprotein- TG (µmol/l) The synthesis of sugar into fat Increased de novo lipogenesis (DNL) Synthesis of fatty acids from non-lipid precursors Test meal containing: [U ]fructose or [U ]glucose Fructose Newly made fatty acids (from fructose) appearing in VLDL-TG P=0.045 Glucose hong et al Am J lin Nutr (2007) Time (min) Test meal: mixed meal with 0.75 g sugar/kg body weight and 0.5g oil/kg body weight

24 onsiderations and onclusions Stable-isotope tracers offer the possibility to trace the fate of dietary fatty acids The partitioning of dietary fatty acids into lipid pools needs to be further explored to understand their usefulness as biomarkers onsideration should be given for the adipose tissue depot that biopsies are taken Fatty acid ratios, particularly the lipogenic index need to be used with caution

25 Thank you! The volunteers OxLip Group and RU Fredrik Karpe Sandy Humphreys Siobhan McQuaid Mary hong amilla Pramfalk atriona McNeil harlotte Green Marje Gilbert amilla Pramfalk Louise Dennis Rachel raven-todd Jane heeseman Sue Beatty Keith Frayn

27 (mol%) Fatty acid composition: Adipose Tissue Abdominal Gluteal * * * * Pinnick K et al Diabetes (2012)

28 Subcutaneous adipose tissue: abdominal vs gluteofemoral Meal Meal Abdominal a.t. Abdominal a.t. Femoral a.t. Femoral a.t. McQuaid et al (2010) Diabetes

Blood fatty acids understanding the relevance of different tissue fractions and interpreting circulating concentrations.

$Blood fatty acids understanding the relevance of different tissue fractions and interpreting circulating concentrations.$ Blood fatty acids understanding the relevance of different tissue fractions and interpreting circulating concentrations Leanne Hodson Fatty acid composition as a biomarker of intake Complements dietary